反義寡核苷酸(antisense oligonucleotide, ASO) 是一種合成型寡核苷酸，具有與特定訊息核糖核酸 (messenger ribonucleic acid, mRNA) 涵義股互補的序列。由其衍生發展之ASO 藥品，是一種新型態之基因治療藥物。在與標的基因mRNA 結合後，ASO藥品藉由使mRNA 分解、調控外顯子的剪接、抑制微小核糖核酸、或降低mRNA 的穩定度等機轉控制基因的表現，達到治療遺傳性疾病的效果。ASO 藥品必須搭配適當的遞送與細胞攝取機制，方能使寡核苷酸分子不受細胞內外核酸酶的分解，穿透生理屏障的阻隔，最終到達目標細胞中產生作用。2016 年美國食品與藥物管理局 (U.S.Food and Drug Administration) 分別核准nusinersen 與eteplirsen 使用於脊髓性肌肉萎縮症與裘馨氏肌肉失養症，宣告ASO 藥品開始實際使用於治療遺傳性神經疾病。基於其針對病因處置的特性與藥理機轉可變性的優點，ASO 藥品勢將在神經系統疾病的治療扮演重要的角色。本文介紹ASO 藥品的藥理作用機轉，施用方式，控制目標細胞攝入藥物之機制，與安全性等基礎知識，並討論ASO 藥品使用於治療遺傳性神經疾病的現況，與對於其治療疾病領域擴展的展望。
Antisense oligonucleotide (ASO) is a synthetic short-stretch of nucleic acid sequence, which is complimentary to a part of sense strand of selected messenger ribonucleic acid (mRNA). Therapeutic ASO is a novel treatment modality in gene therapy. After binding to the targeted mRNA, therapeutic ASO controls expression of the gene through mRNA degradation, exonic splicing modulation, micro-RNA inhibition, or reducing mRNA stability to achieve the effect of treatment for inherited diseases. However, ASO must be matched with appropriate delivery and cellular uptake mechanisms to prevent its decomposition by intracellular and extracellular nucleases, to penetrate the physiological barriers, and finally to reach the target tissue to take effect. In 2016, the U.S. Food and Drug Administration approved nusinersen and eteplirsen for spinal muscular atrophy and Duchenne muscular dystrophy respectively, which declared the beginning of ASO treatments in inherited neurological diseases. With the advantages of etiology-directed management and pharmacological mechanism variability, therapeutic ASO may revolutionize the field of therapeutic strategy in neurology. This review introduces the pharmacology, the mechanisms of deliveryand uptake by target cell and the safety of therapeutic ASO, as well as its current uses in the treatment of inherited neurological diseases and the prospect of its future clinical application.
Summited for publication: 2021.4.16; Accepted for publication: 2021.9.8
